3-oxo-11alpha-hydroxy-11, 19-epoxycard-20(22)-enolides and derivatives thereof



U i -d States, Pa

PatentedJuly 1950 3-OXO-1la HYDROXY-l1;19-EPOXYCARD-20(22)- 5 ENOLIDES AND THEREOF John S. Bar-an, Chicago, Ill., assigno'r to G.-D. Searle &

Co., Chicago, 111., a corporation of Delaware No Drawing Filed July'l'o, '19s9,ser.-1so.s21,4s7 19 Claims. chm-239.51

I-The' present invention relates to ainovfel group pas-'7 bageniri derivativesnand, more particu1ar1yjto3 ox0=11w derivatives" thereof. The compounds zrwithryvhichthis' at, ventio'ni is princi ally concerned ,can'be represented as;

those of the general structural The compounds'of this invention can be conveniently prepared by oxidizing ouabagenin 1,19-acetonide with chromic anhydride in pyridine followed by heating with alumina and ethanol. The resulting 3,11-di0xo-513,14,3, l9-trihydroxycarda-l,20(22)-dieno1idep is hydrogenated in the present of palladium-on-charcoal, typically in epoxycard-20(22)-enolide. As is characteristic for the compounds of the foregoing structural formula in which R represents hydrogen, this product exists in an equilibmixture with the 3,11-dioxo-5p,14,19-trihydroxycard-20(22)-enolide of the structural formula 'Weight. I

S hydrOXy deriVati e'is readily converted to the-4 derivative by heating alone or with an alkanoic acid such as acetic acid. [If this reaction is carried out in an alkanol ROI-I and in the presenceof an acid catalyst,

such as an alkanesulfonic acid or an arylsulfonic acid, there is formed a 3-oxo-lla-alkoxy-l1,19-epoxy-14p-hydroxycarda-4,20(22 dienolide of the structural formula These carda-4,20(22)-dienolides are conveniently converted r too the card-20( 2 2)-enolides by hydrogenation, typically; using palladium-on charcoal a catalyst." Ihe lla-alkoxy "group 'can be changed to a hydroxy group by'jreatment with aqueousacid. Theforegoing l 4 -hy-" droxy compounds with or without a A unsaturation are conveniently dehydrated to the-A analogs by treatnrent with pyridine'and athionyl halide. Again a lla-alkoxy group can be dealkylat'ed by'hydrolysis with aqueous acid; lThe A -unsaturation can be'removed by hydro genation, typically in the presence of palladium-on-char- 'Ihe 3-oxoca'rd-20( 22')-enolides of this invention are conveniently converted to the corresponding 3fl-hydroxy derivatives by reduction with sodium borohydride.

,Thecompounds which' constitute this invention andtheir preparation will appar more fully from i a c n; 1

sideration ofthe [following examples which are given for purposes of illustration only and are not to be construed as limitingstheinvention in spirit or inscope. In these examples guantities are; indicated parts by I I a 2 i .v A mixture ofl30 partsof chromic anhydride and 400 parts of pyridine is prepared adding the chromic anh'ydride to the pyridine Withstir'ring over a period of one hour at 15-20 C. To this mixture is added a slurry v of 30 parts of ouabagenin-1,19-acetonide.and 400 parts of pyridine.

day, it is diluted with 1500-parts of chloroform and After thermixtur'e has been stirred for one filtered 'Ifhe filtrate is extracted with SOQ parts of saturated aqueous solution of sodium bicarbonate; dried over sodium sulfate, .and taken; todryness ,under vacuum. The residue 1's diss'olved in 1000 parts rea er andjthe solutionfis'stirred at reflux for 1 hour with 290" parts off basic alumina. The mixture is filtercd'and the alumina"; is extracted with hot ethanol; the combined filtrate and; extract is concentrated under vacuum to a smalltvolumeQ The crystalline product" is collectedjon a filter, washed I "with ethanol and driedflat 60 c; The 3,1l-dioxo-5fl,

l4 8,1Q-trihydroXycarda-LZO(22)-dienolide thusbbtainedf melts :at about -200". 0. a

5 Amixtureof'z parts ,of this product, IO O parts of ethaf' nol and 0.2 part'of 215% pa1ladium on-charcoa1 :catalystjf ii is'stirred in an atmosphereof hydrogen until one riilj la'r equivalent of hydrogen is; absorbed. :Then the-mixv ture is diluted methanol until the" product which Q. precipitates 'partially during the T hydrogenation 'is,;dis

solved. The mixture is then filtered and the .filtrat i concentrated un'der vacuum at 25 C. to a small volume,

3 Theresulting solid is collected on a filter, washed with methanol and dried. Crystallization from acetone-methanol yields 3-oxo-5/8,11a,14,6-trihydroxy-11,19-epoxyoard-20(22)-enolide which melts at about 178- -181 C. Infrared maxima observed at 2.82, 2.90, 3.38, 5.69477, 5186, 6:13, 8.61; 9.73, 10.30, and 11.07 microns. A methanolic solution shows an ultraviolet maximum at 218 millimiorons- With an extinction coeflicient of about 17,300; The-compoundisin equilibrium with 3,11-dioxo- B, 14 3,19=trihydroxycard-20( 22 -enolide. The

mixture of p 2, parts of ,3,-oxo-5e,-11e,14 8-trihydroxy- 11, 1 9 epoxycard-20(22)-enolide and 10 parts of acetic: acidgisrefiuxedfor 10 minutes and then evaporated todryneSsunder-vacuum. The residue is triturated with acetoneand petroleum ether to yield a crystalline products This is collected by filtration, washed with acetone and ,dried. Crystallization of the crude productv from acetone yields.

Infrared maxima are observed at 2.89, 3.38, 5.71, 5.83, 6.02, 6.l6, 8,70,-9.71, 11.30, 11.56, and 12.30 microns. A methanolic solution shows ultraviolet maxima at 218 and 244millimierons-with extinction coeflicientsof about 20,000 and,14;300, respectively. The compound, in its epoxide form,-- has the-structural formula Example 3 A soluti'on of 6 parts of 3-oxo-11a,14;3-dihydroxy-11, 19-epoxycarda-4,20(22) dienolide, 60 parts of methanol and 0.5 part of p-toluenesulfonic acid is stirred for several hours and-,thenconcentrated to a small volume. The solid, which precipitates is collected. by filtration, washed withmethanol, anddried. Crystallization from ethanol yie1ds. ,3-oxo+11a-meth0xy 11,19 epoxy 14/3 hydroxycarda.-4,20(22) -dienolide which melts .at about -25 8-261 C. Infrared.- maxima areobserved at 2.82, 3.40, 5.77, 6.02 6.18,,7.69, 8.37, 9.09, 10.36, and 11.64.microns.

A methanolic solution shows ultraviolet maxima at 219 and 240 vmillimicrons withextinction coeflicientsof :about 22,000and 17,500, respectively. The specific rotation of a 1% chloroform solutiona is +149.8.

Substitution-of 7.0 parts,.ol: ethanol for the. methanol usedin the, preceding. process, yields 3-oxo-1 la -ethoxy 11, 19-epoxy=1413 hydroxycardae4,20( 22) -dienolide. I

at ahout, 219.,and 240millimicronswith moleculan extinccem-- pounds "thus' inequilibrium have the structural formulas" 3-oxo-1 1a, 14 8-dihydroxy-1 1,19-epoxy carda-4,2 O(22)-dienolide melting at about 248-250 C..

Ultraviolet -maxima, are. shown by a methanolic solution;

tion coeificients of about 21,800 and 17,300, respectively. The compound has the structural formula Example 4 A. mixture of 2 parts of 3,11-dioxo-5p,14;3,19-trihydroxycarda-1,20(22);dienoligle, ,100 parts. of methanol, and 0.2 part ofja ,5%' palladium-on-charcoal catalyst is stirred-in anatmosphere of hydrogen until one molecular equivalent ofhydrogen hasbeen absorbed. The mixture.

is then diluted with methanoljuntilthe productwhichprecipitates partially during the hydrogenationis dissolved, The filtrate is concentrated to a small'volume and then 0.2 part of p-toluenesulfonic acid is added. The solution which results is permitted to stand at room temperature for 12 hours and is then concentrated to a smaller volume 7 and cooled. The solid is collected by filtration, washed withmethanol and dried. The 3-oxo-11a-methoxy-1L19- epoxy-l4fl-hydroxycarda-4,20(22)-dienolide thus obtained has the same-physical properties as the methoxy derivative of the preceding example.

Example 5 A mixture of 4 parts of 3-oxo-11a-methoxy-1L19- epoxy-14/8-hydroxycarda-4,20(22)-dienolide, 0.4 part of 5% palladium-on-charcoal catalyst and parts of methanol is stirred in an atmosphere of hydrogen until one equivalent, of hydrogen is absorbed.v The mixture isgthen Th a? crude residue-is, recrystallized from. methanol toyield? filtered and the, filtrateis evaporated to. dryness.

20(22) -e1,1olide, melting atabout; 228-230, Infrared. maxima are observedyat 2.83," 3.41, 5.77-5-.83-, 6.17, 8.55,; A methanolic IniCl OIlS- solution shows an ultraviolet-,maximum at' 217 millia microns with; an extinetion coefiicient offabout- 16,640;v

he. compound hasathestructuralaformula By substitution of 3-oxo-1la-ethoxy-l1,19-epoxy-14phydroxycarda-4,20(22)-dienolide as a starting material there is obtained 3-oxo-1la-ethoxy-l1,19-epoxy-14fl-hydroxycard-20(22)'-enolide. efficient of a methanolio solution has a maximum at 217 millirnicrons which is about. 16,700.

. Example 6 A mixture of 2 parts of 3-oxo-11a-methoxy-1Ll9- epoxy- 14/3-hydroxycard-20(22)-enolide, 0.2 part of ptoluenesulfonic acid, 50 parts of acetone and 5 parts of water is stirred for 2 hours. The crystalline precipitate is collected on a filter, washed w-ith acetone and dried.

The molecular extinction co-.

There. is thus obtained 3 x0 1la,l4;3-dihydroxy ll,l9- epoxycard-20(22)-eno1ide which melts at abo1 1t 225- 228 C. Infrared maxima are observed at 2.89, 2.93, 3.39, 5.75, 5.88, 6.14, 8.60, 9.25, 9.72, 10.20, 11.10and 11.53 microns A methanolic solution shows a maximum at 217 millimicrons with an extinction coetficient of about 17,700 The specific rotation of a pyridine solution is +6652 The compound, in its epoxy form, has the structural formula I p i V The same compound can likewise be'obtained by sub jecting 3-oxo-1la,l4/3-dihydroxycarda-4,20(22)-dienolide to the procedure of Example 5.

Example 7 To a solution of l part of 3-oxo-llu-methoxy-1L19- epoxy-l4fl-hydroxycard-20(22)-enolide in 5 parts of pyridine is added at 0 C. a solution of 3 parts of thionyl v chloride and parts ofpyridine. After 5 minutesthe mixture is diluted with chloroform, washed with aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to dryness under vacuum. -=Trituration of'the residue in methanol yields 3-oxy-11a-methoxy-ll,19-

epoxycardal4,20(22)-dienolide., Infrared maxima are observed at 3.39, 5.72, 5.84, and 6.13-microns:,

Substitution of' the llu-ethoxy homolog asfa-starting 7 material yields' 3 0x041l'a-ethoxy ll,l9-epoxycardasl4,

20(22)-dienolide, a compound which shows infrared maxima at about 3.4, 5.72, 5,85, and 6.14micr'ons. It has the structural formula 1 by the procedure of Example 6 yields 3-oxo-llm-hydroxy- 1 1,19-epoxycarda-14,20(22) -dienolide which shows infrared maxima at about 2.91, 3.39, 5.73, 5. 85, and 6.14 microns.

Example 8" To a mixture of 20 parts of 3-oxo-1lot-methoxy-1L19- epoxy-l4fl-hydroxycarda 4,2O(22)-dienolide and 100 l-partsof pyridine is added. a; solution of 6.4 parts of thionyl' chloride in 25 parts ofjpyridine at 0 C. After 10 minutes the solutionis dilutedwith 350 parts of chloroform. The organic solution: is washed with saturated aqueous sodium bicarbonate, dried over sodium. sulfate and evaporated to dryness under vacuum. Crystallization of-the'crude product from dichlorom'ethane yields 3-oxo- 11 methoxy 11,19 epoxycarda 4,l4,20(22) trienolide melting at about 212214 C. Infrared maxima are observed at 3.44, 5.72, 6.05, 6.14, 6.22, 9.30, 9.51, 10.05, 11.62, and 12.50 microns. A. methanolic' solution p p 65 Hydrolysis of the foregoingllu-methoxy derivative.

v} tion is. then added 0.05 part of p-toluenesulfonic acid. The solution is concentratedv until crystallization starts,-

audit is then cooled. The crude product is "collected by structural formula lar extinction coefiicients of about shows ultra-violet maximaat 217 and 241 millimicrons with molecular extinction coefficients of about 20,200 and 18,500, respectively. The specific rotation of a, 1% chloroform solution is +1'19.5. ,Theeompound has, the

Substituting as a starting material 3-oxo-11 -ethoxy- 11,19-epoxy-14fl-hydroxycarda-4,20(22)-dienolide there is obtained 3 oxo 11oz ethoxy-ll,19-epoxycarda-4,14, 20(22)-trienolide. The ultraviolet absorption spectrum shows maxima at 217 and 241 millimicrons with molecu- 20,000 and 18,500, respectively.

Example 9 V A mixture of 4 parts of 3-oxo-11a-methoxy-1Ll9- epoxycarda-4,l4,20(22)-trienolide, 40 parts of ethyl acetate, 40 parts of methanol and 1 part of 5% palladium-on-carcoal is stirred in an atmosphere of hydrogen until two equivalents have been absorbed. The mixture is filtered and the filtrate is concentrated to a small volume. The residue which precipitates is collected by 51 filtration, washed with methanol and dried. Crystallization of the crude product from dichloromethane in card-20(22)-enolide which melts at about 192194 when heated rapidly. When heated slowly it appears to soften at" about C. and then meltsat about 230250 C.- Infrared maxiina are observed "at 3.40, 5.70, 5.83, 6.15,i

8.70, 9.88, 11.20and '11.50microns. A methanolic solution shows. an ultraviolet maximum at'217 millimicrons with *an' extinction coeificient of about 15,000. The, specific rotation of a 1% chloroform solution is'+126.5

The: compound has the structural formula filtratio'n, washed with acetone and dried. Crystallization from acetone yields the product which exists primarily in the non-epoxidal form as 3,11 dioxo 19 hydrocarda- 4,14,20(22)-trieno1ide. It melts at about 231-233 C.

and 23.7 millicrons with molecular extinction coeiiicientsv of about 20,600 and 18,200, respectively.

Example 11 To a warm solution of 1 part of 3-oxo-lla-methoxy- 11,19-6POXY-50L,14d-C31'd720(22)-Bl1O1ide in 50 parts of acetone are added first 10 parts of water and then 0.05 part of p-toluenesulfonic acid. The solution is concentrated until crystallization ensues and then is cooled. The crude product is collected by-filtration, washed with acetone and dried. Crystallization from dichloromethane yields 3-OXO-11OL hydroxy 11,19 epoxy 50:,1404 card- 20(22)-enolide melting at about 225-22 7 C. Infrared maxima are observed at about 2.92, 3.40, 5.75, 5.83, 6.15, 9.21, 9.40, 11.09 and 11.53 microns. A. methanolic solution shows an ultraviolet maximum at about 215. millimicrons with an' extinction of about 17,000; The compound, in its epoxidal structure, has the. formula H CH:

Extzrrzple 12 A mixture of 2' parts of 3-oxo+11a-methoxy'-11,l9- epoxy-a,14m-card 20(22)-eno]ide, 1 part of sodium borohydride and 100 partsz'of a 4:1 mixture of'dioxane and Water is stirred for 45 minutes at room temperature and then acidified with 2-N sulfuric acid. The mixture diluted -with water and concentrated under vacuum.- The remaining solution is extracted thoroughly. with Example 13 A mixture of 1 part of 3-oxo-11a-hydroxy-11,19-epoxy- 5oz,14a-card-20(22)-enolide, 1 part of sodium borohydride and 100 parts of a 4:1 mixture of dioxane and water is stirred for 2 hours and then acidified with 2-N sulfuric acid. extracted. with chloroform. The chloroform extract is washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and evaporated to dryness. Trituration of theresidue with acetone yields a crystalline solid which is recrystallized from acetone to yield 3,8,11B,19- 1IihydIOXy-5a,1'4zx-C2lId-Z0(22)-6n011d melting at about 277-278 C. infrared maxima are observed at 2.83, 2.94, 3.40, 5.72, 6.15, 7.98, 11.20 and 11.78- microns. The specific rotation of 21 methanol solution is +48.4.

The same'product can also be. obtained by the sodium.

borohydride reduction. of the foregoing procedure when there is used as a starting material 3,6,1l-adihy'dIQXY- 1'1,19'-'epoxy-5a,14a-eard-20(22)enolide..

The mixture is diluted with water and 7 5 trienolide.-

What is claimed is: Y Y h '1. A member of the class-consisting. of-the compounds of the formula i and their A and A derivatives, wherein R is a member of the class consisting of. hydrogen and lower alkyl radicals. 5

2. 3-oxo-1 IOC-hYdFOXY'i1,19'epUXy-51Z,14lX-C3I'd'20(22)- enolide.

3. A compound of the structural formula (lower alkyD-Q' OH! I (lower alkyD-O CH3 6. 3-oxo-11a-methoxy-1L19 epoxycarda 14,20(22)- 1 dienolide.

7. 3-oxo-11a-hydroxy-1L19 epoxycarda dienolide.

I 8. A compound of the'structuralformula' I 9.. 3-oxo-l1'a-methoxy-1L19 Q epoxycarda 4, 14,20;(22)

) '13. A compound of the structural formula 10. A compound of the structural formula wherein R is a member of the class consisting of hydrogen and lower alkyl radicals.

I? 11. 3-oxo-11u-methoxy-1L19 epoxy 145 hydroxycarda-4,20(22)-dienolide.

12. 3 oxo 11a,14fi dihydroxycarda 4,20(22)-dienolide.

wherein R is a member of the class consisting of hydrogen and lower alkyl groups and X is a member of the class consisting of hydrogen and hydroxyl radicals.

14. 3-0X0-5[3,11a,14fi trihydroxy-11,19 epoxycard- 20 (22 -enolide.

15. 3-oxo ;,145 dihydroxy 11,19 epoxycard- 20(22)-enolide.

16. 3-0X0-11u methoxy 11,19 epoxy-Mfi-hydroxycard-20 (22) -enolide.

17. 33,110; dihydroxy-l1,19-epoxy-5or,14a card-20- 22) -en01ide.

18. 3,11 dioxo 19 hydroxycarda 4,14,20(22) trienolide. I

'19. 313,115,19 trihydrQXy-Su,14a-card-20(22)-enolide.

References Cited in the file of this patent Tamm et al.: Experientia, vol. 13, No. 5, pages -7, 1957.

Patent No. 2,946,786

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION July 26, 1960 John S. Baran It is hereby certified that error appears in the printed specification of tlie above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column l line 52 for "present," read presence column 6 line 74,, for "hydrocarda" read hydroxycar'da Signed and sealed this 4th day of April 1961.

SEAL g ERNEST w. SWIDER xmmzexx ARTHUR w. CROCKER Attes ting Oflicer Acting Commissioner of Patents 

1. A MEMBER OF THE CLASS CONSISTING OF THE COMPOUNDS OF THE FORMULA 